Huang Jinghan, Wang Yixuan, Stein Thor D, Ang Ting Fang Alvin, Zhu Yibo, Tao Qiushan, Lunetta Kathryn L, Mez Jesse, Au Rhoda, Farrer Lindsay A, Qiu Wei Qiao, Zhang Xiaoling
Boston University Chobanian & Avedisian School of Medicine.
Boston University School of Public Health.
Res Sq. 2023 Sep 28:rs.3.rs-3376348. doi: 10.21203/rs.3.rs-3376348/v1.
Previous study shows that monocyte chemoattractant protein-1 (MCP-1), which is implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption, modulates the genetic risks of AD in established AD loci.
In this study, we hypothesized that blood MCP-1 impacts the AD risk of genetic variants beyond known AD loci. We thus performed a genome-wide association study (GWAS) using the logistic regression via generalized estimating equations (GEE) and the Cox proportional-hazards models to examine the interactive effects between single nucleotide polymorphisms (SNPs) and blood MCP-1 level on AD in three cohorts: the Framingham Heart Study (FHS), Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study/Memory and Aging Project (ROSMAP).
We identified SNPs in two genes, neuron navigator 3 (, also named Unc-53 Homolog 3, rs696468) (p < 7.55×10) and Unc-5 Netrin Receptor C ( rs72659964) (p < 1.07×10) that showed an association between increasing levels of blood MCP-1 and AD. Elevating blood MCP-1 concentrations increased AD risk and AD pathology in genotypes of (rs696468-CC) and (rs72659964-AT + TT), but did not influence the other counterpart genotypes of these variants.
and are homologs and may increase AD risk through dysregulating the functions of neurite outgrowth and guidance. Overall, the association of risk alleles of and with AD is enhanced by peripheral MCP-1 level, suggesting that lowering the level of blood MCP-1 may reduce the risk of developing AD for people with these genotypes.
先前的研究表明，单核细胞趋化蛋白-1（MCP-1）参与外周促炎级联反应和血脑屏障（BBB）破坏，可调节已确定的AD基因座中AD的遗传风险。
在本研究中，我们假设血液中的MCP-1会影响已知AD基因座以外的遗传变异的AD风险。因此，我们通过广义估计方程（GEE）的逻辑回归和Cox比例风险模型进行了全基因组关联研究（GWAS），以检验单核苷酸多态性（SNP）与血液MCP-1水平在三个队列中的AD交互作用：弗雷明汉心脏研究（FHS）、阿尔茨海默病神经影像学倡议（ADNI）和宗教团体研究/记忆与衰老项目（ROSMAP）。
我们在两个基因中鉴定出SNP，即神经导航蛋白3（也称为Unc-53同源物3，rs696468）（p < 7.55×10）和Unc-5神经纤毛蛋白受体C（rs72659964）（p < 1.07×10），它们显示血液MCP-1水平升高与AD之间存在关联。血液MCP-1浓度升高会增加(rs696468-CC)和(rs72659964-AT + TT)基因型的AD风险和AD病理，但不影响这些变异的其他对应基因型。
和 是同源物，可能通过失调神经突生长和导向功能增加AD风险。总体而言， 和 的风险等位基因与AD的关联因外周MCP-1水平而增强，这表明降低血液MCP-1水平可能会降低这些基因型人群患AD的风险。
